The aims of the investigation are to examine the role of histones in the regulation of DNA synthesis and to determine the degree of change in histone metabolism in neoplasia. The nature of the coupling between histone and DNA synthesis will be studied by use of compounds which show selectivity for the inhibition of protein of DNA synthesis. By comparison of regenerating liver and hepatomas, it may be possible to identify changes which are more characteristic of malignant than normal growth. Hepatomas of the Morris series will be used to provide a spectrum of growth rates. Possible variation in drug sensitivity will be investigated in nuclei differing in ploidy in normal and neoplastic tissues. In attempts to elucidate the mechanisms of action of histones on DNA synthesis particular attention will be directed to the fl and fl zero histones prepared from liver and hepatomas. In situations in which an imbalance is created in histone and DNA synthesis, accompanying changes in metabolism will be examined for indications of changes which restore a normal balance in these chromosomal constituents. BIBLIOGRAPHIC REFERENCES: M.A. Lea, M.R. Koch and H.P. Morris Decreased uptake of orotate in kidney tumors. Cancer Biochem. Biophys. 1, 265-268 (1976). M.A. Lea, M.R. Koch, B. Beres and V. Dayal. Divergent effects of cyanate on aminoacid and phosphate uptake by liver and hepatoma. Biochim. Biophys. Acta 474, 321-328 (1977).